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Full-Text Articles in Medicinal-Pharmaceutical Chemistry

Dengue Virus Ns2b/Ns3 Protease Inhibitors Exploiting The Prime Side, Kuan-Hung Lin, Akbar Ali, Linah Rusere, Djade I. Soumana, Nese Kurt Yilmaz, Celia A. Schiffer Jul 2017

Dengue Virus Ns2b/Ns3 Protease Inhibitors Exploiting The Prime Side, Kuan-Hung Lin, Akbar Ali, Linah Rusere, Djade I. Soumana, Nese Kurt Yilmaz, Celia A. Schiffer

Celia A. Schiffer

The mosquito-transmitted dengue virus (DENV) infects millions of people in tropical and subtropical regions. Maturation of DENV particles requires proper cleavage of the viral polyprotein, including processing of 8 of the 13 substrate cleavage sites by dengue virus NS2B/NS3 protease. With no available direct-acting antiviral targeting DENV, NS2/NS3 protease is a promising target for inhibitor design. Current design efforts focus on the nonprime side of the DENV protease active site, resulting in highly hydrophilic and nonspecific scaffolds. However, the prime side also significantly modulates DENV protease binding affinity, as revealed by engineering the binding loop of aprotinin, a ...


Interdependence Of Inhibitor Recognition In Hiv-1 Protease, Janet L. Paulsen, Florian Leidner, Debra A. Ragland, Nese Kurt Yilmaz, Celia A. Schiffer Jun 2017

Interdependence Of Inhibitor Recognition In Hiv-1 Protease, Janet L. Paulsen, Florian Leidner, Debra A. Ragland, Nese Kurt Yilmaz, Celia A. Schiffer

Celia A. Schiffer

Molecular recognition is a highly interdependent process. Subsite couplings within the active site of proteases are most often revealed through conditional amino acid preferences in substrate recognition. However, the potential effect of these couplings on inhibition and thus inhibitor design is largely unexplored. The present study examines the interdependency of subsites in HIV-1 protease using a focused library of protease inhibitors, to aid in future inhibitor design. Previously a series of darunavir (DRV) analogs was designed to systematically probe the S1' and S2' subsites. Co-crystal structures of these analogs with HIV-1 protease provide the ideal opportunity to probe subsite interdependency ...


A Nmr Experiment For Simultaneous Correlations Of Valine And Leucine/Isoleucine Methyls With Carbonyl Chemical Shifts In Proteins, Vitali Tugarinov, Vincenzo Venditti, G. Marius Clore Jan 2014

A Nmr Experiment For Simultaneous Correlations Of Valine And Leucine/Isoleucine Methyls With Carbonyl Chemical Shifts In Proteins, Vitali Tugarinov, Vincenzo Venditti, G. Marius Clore

Vincenzo Venditti

A methyl-detected ‘out-and-back’ NMR experiment for obtaining simultaneous correlations of methyl resonances of valine and isoleucine/leucine residues with backbone carbonyl chemical shifts, SIM-HMCM(CGCBCA)CO, is described. The developed pulse-scheme serves the purpose of convenience in recording a single data set for all Ileδ1, Leuδ and Valγ (ILV) methyl positions instead of acquiring two separate spectra selective for valine or leucine/isoleucine residues. The SIM-HMCM(CGCBCA)CO experiment can be used for ILV methyl assignments in moderately sized protein systems (up to ~100 kDa) where the backbone chemical shifts of 13Cα, 13Cβ and 13CO are known from prior NMR ...


Structure, Dynamics And Biophysics Of The Cytoplasmic Protein–Protein Complexes Of The Bacterial Phosphoenolpyruvate: Sugar Phosphotransferase System, Vincenzo Venditti Jan 2013

Structure, Dynamics And Biophysics Of The Cytoplasmic Protein–Protein Complexes Of The Bacterial Phosphoenolpyruvate: Sugar Phosphotransferase System, Vincenzo Venditti

Vincenzo Venditti

The bacterial phosphotransferase system (PTS) couples phosphoryl transfer, via a series of bimolecular protein–protein interactions, to sugar transport across the membrane. The multitude of complexes in the PTS provides a paradigm for studying protein interactions, and for understanding how the same binding surface can specifically recognize a diverse array of targets. Fifteen years of work aimed at solving the solution structures of all soluble protein–protein complexes of the PTS has served as a test bed for developing NMR and integrated hybrid approaches to study larger complexes in solution and to probe transient, spectroscopically invisible states, including encounter complexes ...


Structural Basis For Enzyme I Inhibition By Α-Ketoglutarate, Vincenzo Venditti, Rodolfo Ghirlando, G. Marius Clore Jan 2013

Structural Basis For Enzyme I Inhibition By Α-Ketoglutarate, Vincenzo Venditti, Rodolfo Ghirlando, G. Marius Clore

Vincenzo Venditti

Creating new bacterial strains in which carbon and nitrogen metabolism are uncoupled is potentially very useful for optimizing yields of microbial produced chemicals from renewable carbon sources. However, the mechanisms that balance carbon and nitrogen consumption in bacteria are poorly understood. Recently, α-ketoglutarate (αKG), the carbon substrate for ammonia assimilation, has been observed to inhibit Escherichia coli enzyme I (EI), the first component of the bacterial phosphotransferase system (PTS), thereby providing a direct biochemical link between central carbon and nitrogen metabolism. Here we investigate the EI-αKG interaction by NMR and enzymatic assays. We show that αKG binds with a KD ...


Conformational Selection And Substrate Binding Regulate The Monomer/Dimer Equilibrium Of The C-Terminal Domain Of Escherichia Coli Enzyme I, Vincenzo Venditti, G. Marius Clore Jan 2012

Conformational Selection And Substrate Binding Regulate The Monomer/Dimer Equilibrium Of The C-Terminal Domain Of Escherichia Coli Enzyme I, Vincenzo Venditti, G. Marius Clore

Vincenzo Venditti

The bacterial phosphotransferase system (PTS) is a signal transduction pathway that couples phosphoryl transfer to active sugar transport across the cell membrane. The PTS is initiated by the binding of phosphoenolpyruvate (PEP) to the C-terminal domain (EIC) of enzyme I (EI), a highly conserved protein that is common to all sugar branches of the PTS. EIC exists in a dynamic monomer/dimer equilibrium that is modulated by ligand binding and is thought to regulate the overall PTS. Isolation of EIC has proven challenging, and conformational dynamics within the EIC domain during the catalytic cycle are still largely unknown. Here, we ...


Measuring The Dynamic Surface Accessibility Of Rna With The Small Paramagnetic Molecule Tempol, Vincenzo Venditti, Neri Niccolai, Samuel E. Butcher Jan 2008

Measuring The Dynamic Surface Accessibility Of Rna With The Small Paramagnetic Molecule Tempol, Vincenzo Venditti, Neri Niccolai, Samuel E. Butcher

Vincenzo Venditti

The surface accessibility of macromolecules plays a key role in modulating molecular recognition events. RNA is a complex and dynamic molecule involved in many aspects of gene expression. However, there are few experimental methods available to measure the accessible surface of RNA. Here, we investigate the accessible surface of RNA using NMR and the small paramagnetic molecule TEMPOL. We investigated two RNAs with known structures, one that is extremely stable and one that is dynamic. For helical regions, the TEMPOL probing data correlate well with the predicted RNA surface, and the method is able to distinguish subtle variations in atom ...


Structure And Thermodynamics Of A Conserved U2 Snrna Domain From Yeast And Human, Dipali G. Sashital, Vincenzo Venditti, Courtney G. Angers, Gabriel Cornilescu, Samuel E. Butcher Jan 2007

Structure And Thermodynamics Of A Conserved U2 Snrna Domain From Yeast And Human, Dipali G. Sashital, Vincenzo Venditti, Courtney G. Angers, Gabriel Cornilescu, Samuel E. Butcher

Vincenzo Venditti

The spliceosome is a dynamic ribonucleoprotein complex responsible for the removal of intron sequences from pre-messenger RNA. The highly conserved 5′ end of the U2 small nuclear RNA (snRNA) makes key base-pairing interactions with the intron branch point sequence and U6 snRNA. U2 stem I, a stem–loop located in the 5′ region of U2, has been implicated in spliceosome assembly and may modulate the folding of the U2 and U6 snRNAs in the spliceosome active site. Here we present the NMR structures of U2 stem I from human and Saccharomyces cerevisiae. These sequences represent the two major classes of ...